Skip to main content
SpringerLink
Log in

Thermo-Sensitive Liposome co-Loaded of Vincristine and Doxorubicin Based on Their Similar Physicochemical Properties had Synergism on Tumor Treatment

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

An Erratum to this article was published on 28 June 2016

Abstract

Purpose

To develop vincristine (VCR) and doxorubicin (DOX) co-encapsulated thermo-sensitive liposomes (VD-TSL) against drug resistance, with increased tumor inhibition rate and decreased system toxicity, improving drug targeting efficiency upon mild hyperthermia (HT) in solid tumor.

Methods

Based on similar physicochemical properties, VCR and DOX were co-loaded in TSL with pH gradient active loading method and characterized. The time-dependent drug release profiles at 37 and 42°C were assessed by HPLC. Then we analysed the phospholipids in filtrate after ultrafiltration and studied VD-TSL stability in mimic in vivo conditions and long-time storage conditions (4°C and −20°C). Cytotoxic effect was studied on PANC and sw-620 using MTT. Intracellular drug delivery was studied by confocal microscopy on HT-1080. In vivo imaging of TSL pharmacokinetic and biodistribution was performed on MCF-7 tumor-bearing nude mice. And therapeutic efficacy on these xenograft models were followed under HT.

Results

VD-TSL had excellent particle distribution (about 90 nm), high entrapment efficiency (>95%), obvious thermo-sensitive property, and good stability. MTT proved VD-TSL had strongest cell lethality compared with other formulations. Confocal microscopy demonstrated specific accumulation of drugs in tumor cells. In vivo imaging proved the targeting efficiency of TSL under hyperthermia. Then therapeutic efficacy revealed synergism of VCR and DOX co-loaded in TSL, together with HT.

Conclusion

VD-TSL could increase drug efficacy and decrease system toxicity, by making good use of synergism of VCR and DOX, as well as high targeting efficiency of TSL.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

Abbreviations

CVD-TSL:

Thermo-sensitive liposomes containing Cou-6, vincristine and doxorubicin

Cy5-TSL:

Thermo-sensitive liposomes containing Cy5

DOX:

Doxorubicin

DOX-TSL:

Thermo-sensitive liposomes containing doxorubicin

HT:

Hyperthermia

TSL:

Thermo-sensitive liposomes

VCR:

Vincristine

VCR-TSL:

Thermo-sensitive liposomes containing vincristine

VD-TSL:

Thermo-sensitive liposomes containing vincristine and doxorubicin

References

  1. Dexter DL, Kowalski HM, Blazar BA, Fligiel Z, Vogel R, Heppner GH. Heterogeneity of tumor cells from a single mouse mammary tumor. Cancer Res. 1978;38:3174–81.

    CAS  PubMed  Google Scholar 

  2. Spremulli E, Dexter D. Human tumor cell heterogeneity and metastasis. J Clin Oncol. 1983;1:496–509.

    CAS  PubMed  Google Scholar 

  3. Wick MR, Scheithauer BW, Weiland LH, Bernatz PE. Primary thymic carcinomas. Am J Surg Pathol. 1982;6:613–30.

    Article  CAS  PubMed  Google Scholar 

  4. Shimosato Y, Kameya T, Nagai K, Suemasu K. Squamous cell carcinoma of the thymus: an analysis of eight cases. Am J Surg Pathol. 1977;1:109–21.

    Article  CAS  PubMed  Google Scholar 

  5. Weide LG, Ulbright TM, LoehrerSr PJ, Williams SD. Thymic carcinoma: a distinct clinical entity responsive to chemotherapy. Cancer. 1993;71:1219–23.

    Article  CAS  PubMed  Google Scholar 

  6. Kwong B, Liu H, Irvine DJ. Induction of potent anti-tumorresponses while eliminating systemic side effects via liposome-anchored combinatorial immunotherapy. Biomaterials. 2011;32:5134–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Siddiqui A, Gupta V, Liu YY, Nazzal S. Doxorubicin and MBO-asGCSoligo nucleotide loaded lipid nanoparticles overcome multidrug resistance in adriamycin resistant ovarian cancer cells (NCI/ADR-RES). Int J Pharm. 2012;431:222–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Pauwels EK, Erba P, Mariani G, Gomes CM. Multidrug resistance in cancer: its mechanism and its modulation. Drug News Perspect. 2007;20:371–7.

    Article  CAS  PubMed  Google Scholar 

  9. Kaufman D, Chabner BA. Clinical strategies for cancer treatment. In: Chabner BA, Longo DL, editors. The role of drugs, cancer chemotherapy and biotherapy,2nd ed. Philadelphia, PA: Lippincott-Raven; 1996. p. 1.

    Google Scholar 

  10. Krishnan V, Rajasekaran AK. Clinical nanomedicine: a solution to the chemotherapy conundrum in pediatric leukemia therapy. Clin Pharmacol Ther. 2014;95:168–78.

    Article  CAS  PubMed  Google Scholar 

  11. Liang XJ, Chen C, Zhao Y, Wang PC. Circumventing tumor resistance to chemo-therapy by nanotechnology, Multi-Drug Resistance in Cancer. Humana Press. 2010. p. 467–488.

  12. Morton SW, Lee MJ, Deng ZJ, Dreaden EC, Siouve E, Shopsowitz KE, et al. A nanoparticle-based combination chemotherapy delivery system for enhanced tumor killing by dynamic rewiring of signaling pathways. Sci Signal. 2014;7:44.

    Article  Google Scholar 

  13. Weiss RB. The anthracyclines: will we ever find a better doxorubicin? Semin Oncol. 1992;19:670–86.

    CAS  PubMed  Google Scholar 

  14. Takemura G, Fujiwara H. Doxorubicin-induced cardiomyopathy from the cardiotoxic mechanisms to management. Prog Cardiovasc Dis. 2007;49:330–52.

    Article  CAS  PubMed  Google Scholar 

  15. Oliveira PJ, Bjork JA, Santos MS, Leino RL, Froberg MK, Moreno AJ, et al. Carvedilol mediated antioxidant protection against doxorubicin induced cardiac mitochondrial toxicity. Toxicol Appl Pharmacol. 2004;200:159–68.

    Article  CAS  PubMed  Google Scholar 

  16. Della PT, Imondi AR, Bernardi C, Podestà A, Moneta D, Riflettuto M, et al. Cardioprotection by dexrazoxane in rats treated with doxorubicin and paclitaxel. Cancer Chemother Pharmacol. 1999;44:138–42.

    Article  Google Scholar 

  17. Stearn WT. Marcel Dekker. In: Taylor WI, Farnsworth NR, editors. The Catharanthus Lkaloids. New York: Plenum; 1975. p. 9.

    Google Scholar 

  18. Zhang H, Wang ZY, Gong W, Li ZP, Mei XG, Lv WL. Development and characteristics of temperature-sensitive liposomes for vinorelbine bitartrate. Int J Pharm. 2011;414:56–62.

    Article  CAS  PubMed  Google Scholar 

  19. Malawista S, Bensch K, Sato H. Vinblastine and griseofulvin reversibly disrupt the living mitotic spindle. Science. 1968;160:770.

    Article  CAS  PubMed  Google Scholar 

  20. Kaplan LD, Deitcher SR, Silverman JA, Morgan G. Phase II study of vincristine sulfate liposome injection (Marqibo) and rituximab for patients with relapsed and refractory diffuse large B-cell lymphoma or Mantle cell lymphoma in need of palliative therapy. Cl Lymph MyelomLeuk. 2014;14(1):37–42.

    Article  Google Scholar 

  21. Deitcher OR, Glaspy J, Gonzalez R, Sato T, Bedikian AY, Segarini K, et al. High-dose vincristine sulfate liposome injection (Marqibo) is not associated with clinically meaningful hematologic toxicity. Cl Lymph MyelomLeuk. 2014;14(3):197–202.

    Article  Google Scholar 

  22. Chatterjee K, Zhang J, Honbo N, Simonis U, Shaw R, Karliner JS. Acute vincristine pretreatment protects adult mouse cardiac myocytes from oxidative stress. J Mol Cell Cardiol. 2007;43:327–36.

    Article  CAS  PubMed  Google Scholar 

  23. Vincristine and Doxorubicin. http://www.drugbank.ca/.

  24. Yatvin MB, Weinstein JN, Dennis WH, Blumenthal R. Design of liposomes for enhanced local release of drugs by hyperthermia. Science. 1978;202:1290–3.

    Article  CAS  PubMed  Google Scholar 

  25. Weinstein JN, Magin RL, Yatvin MB, Zaharko DS. Liposomes and local hyperthermia: selective delivery of methotrexate to heated tumors. Science. 1979;204:188–91.

    Article  CAS  PubMed  Google Scholar 

  26. Yatvin WJ, Dennis WH, Blumenthal R. Design of liposomes for enhanced local release of drugs byhyperthermia. Science. 1978;202:1290–3.

    Article  CAS  PubMed  Google Scholar 

  27. Needham D, Anyarambhatla G, Kong G, Dewhirst MW. A new temperature-sensitive liposome for use with mild hyperthermia: characterization and testing in a human tumor xenograft model. Cancer Res. 2000;60:1197–201.

    CAS  PubMed  Google Scholar 

  28. Lindner LH, Eichhorn ME, Eibl H, Teichert N, Schmitt-Sody M, Issels RD, et al. Novel temperature-sensitive liposomes with prolonged circulation time. Clin Cancer Res. 2004;10:2168–78.

    Article  CAS  PubMed  Google Scholar 

  29. Paulides MM, Bakker JF, Neufeld E, van der Zee J, Jansen PP, Levendag PC, et al. The HYPER collar: a novel applicator for hyperthermia in the head and neck. Int J Hyperth. 2007;23:567–76.

    Article  CAS  Google Scholar 

  30. Smet MD, Heijman E, Langereis S, Hijnen NM, Grull H. Magnetic resonance imaging of high intensity focused ultrasound mediated drug delivery from temperature-sensitive liposomes: an in vivo proof-of-concept study. J Control Release. 2011;150:102–10.

    Article  PubMed  Google Scholar 

  31. Greish K. Enhanced permeability and retention of macro-molecular drugs in solid tumors: a royal gate for targeted anticancer nanomedicines. J Drug Target. 2007;15:457–64.

    Article  CAS  PubMed  Google Scholar 

  32. Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 1986;46:6387–92.

    CAS  PubMed  Google Scholar 

  33. Bae YH, Park K. Targeted drug delivery to tumors: myths, reality and possibility. J Control Release. 2011;153:198–205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mayer LD, Bally MB, Loughrey H, Masin D, Cullis PR. Liposomal vincristine preparations which exhibit decreased drug toxicity and increased activity against murine L1210 and P388 tumors. Cancer Res. 1990;50:575–9.

    CAS  PubMed  Google Scholar 

  35. Kanter PM, Klaich GM, Bullard GA, King JM, Bally MB, Mayer LD. Liposome encapsulated vincristine: preclinical toxicologic and pharmacologic comparison with free vincristine and empty liposomes in mice, rats and dogs. Anti-Cancer Drugs. 1994;5:579–90.

    Article  CAS  PubMed  Google Scholar 

  36. Chen Q, Tong S, Dewhirst MW, Yuan F. Targeting tumor microvessels using doxorubicin encapsulated in a novel thermosensitive liposome. Mol Cancer Ther. 2004;3:1311–7.

    CAS  PubMed  Google Scholar 

  37. Secord AA, Jones EL, Hahn CA, Petros WP, Yu D, Havrilesky LJ, et al. Phase I/II trial of intravenous Doxil (R) and whole abdomen hyperthermia in patients with refractory ovarian cancer. Int J Hyperth. 2005;21:333–47.

    Article  Google Scholar 

  38. Yarmolenko PS, Zhao Y, Landon C, Spasojevic I, Yuan F, Needham D, et al. Comparative effects of thermosensitive doxorubicin-containing liposomes and hyperthermia in human and murine tumours. Int J Hyperth. 2010;26:485–98.

    Article  CAS  Google Scholar 

  39. Ta T, Bartolak-Suki E, Park EJ, Karrobi K, McDannold NJ, Porter TM. Localized delivery of doxorubicin in vivo from polymer-modified thermosensitive liposomes with MR-guided focused ultrasound-mediated heating. J Control Release. 2014;194:71–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Embree L, Gelmon KA, Tolcher AW, Hudon NJ, Heggie JR, Dedhar C, et al. Validation of a high-performance liquid chromatographic assay method for quantification of total vincristine sulfate in human plasma following administration of vincristine sulfate liposome injection. J Pharm Biomed Anal. 1997;16:675–87.

    Article  CAS  PubMed  Google Scholar 

  41. Krawczyk PM, Eppink B, Essers J, Stap J, Rodermond H, Odijk H, et al. Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly(ADP-ribose) polymerase-1 inhibition. Proc Natl AcadSci USA. 2011;108:9851–6.

    Article  CAS  Google Scholar 

  42. Kong G, Anyarambhatla G, Petros WP, Braun RD, Colvin OM, Needham D, et al. Efficacy of liposomes and hyperthermia in a human tumor xenograft model: importance of triggered drug release. Cancer Res. 2000;60:6950–7.

    CAS  PubMed  Google Scholar 

  43. Kong G, Braun RD, Dewhirst MW. Hyperthermia enables tumor-specific nanoparticle delivery: effect of particle size. Cancer Res. 2000;60:4440–5.

    CAS  PubMed  Google Scholar 

  44. de Smet M, Langereis S, van den Bosch S, Grull H. Temperature-sensitive liposomes for doxorubicin delivery under MRI guidance. J Control Release. 2010;143:120–7.

    Article  PubMed  Google Scholar 

  45. Landon CD, Park JY, Needham D, Dewhirst MW. Nanoscale drug delivery and hyperthermia: the materials design and preclinical and clinical testing of Low temperature-sensitive liposomes used in combination with mild hyperthermia in the treatment of local cancer. Open Nanomed J. 2011;3:38–64.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Hossann M, Syunyaeva Z, Schmidt R, Zengerle A, Eibl H, Issels RD, et al. Proteins and cholesterol lipid vesicles are mediators of drug release from thermosensitive liposomes. J Control Release. 2012;162:400–6.

    Article  CAS  PubMed  Google Scholar 

  47. Hossann M, Wiggenhorn M, Schwerdt A, Wachholz K, Teichert N, Eibl H. In vitro stability and content release properties of phosphatidylglycero containing thermosensitive liposomes. Biochim Biophys Acta. 2007;1768:2491–9.

    Article  CAS  PubMed  Google Scholar 

  48. Yang Y, Yang YF, Xie XY, Wang ZY, Gong W, Zhang H, et al. Dual-modified liposomes with a two-photon-sensitive cell penetrating peptide and NGR ligand for siRNA targeting delivery. Biomaterials. 2015;48:84–96.

    Article  CAS  PubMed  Google Scholar 

  49. Johnston MJW, Semple SC, Klimuk SK, Edwards K, Eisenhardt ML, Leng EC, et al. Therapeutically optimized rates of drug release can be achieved by varying the drug-to-lipid ratio in liposomal vincristine formulations. Biochim Biophys Acta. 2006;1758:55–64.

    Article  CAS  PubMed  Google Scholar 

  50. Zhigaltseva IV, Maurer N, Akhong QF, Leone R, Leng E, Wang J, et al. Liposome-encapsulated vincristine, vinblastine and vinorelbine: A comparative study of drug loading and retention. J Control Release. 2005;104:103–11.

    Article  Google Scholar 

  51. USP34-NF29.2011; 4585–887.

  52. Dicheva BM, ten Hagen TLM, Schipper D, Seynhaeve ALB, van Rhoon GC, Eggermont AMM, et al. Targeted and heat-triggered doxorubicin delivery to tumors by dual targeted cationic thermosensitive liposomes. J Control Release. 2014;195:37–48.

    Article  CAS  PubMed  Google Scholar 

  53. Vehoveca T, Obreza A. Review of operating principle and applications of the charged aerosol detector. J Chromatogr A. 2010;1217:1549–56.

    Article  Google Scholar 

  54. Joseph A, Rustum A. Development and validation of a RP-HPLC method for the determination of gentamicin sulfate and its related substances in a pharmaceutical cream using a short pentafluorophenyl column and a charged aerosol detector. J Pharm Biomed. 2010;51:521–31.

    Article  CAS  Google Scholar 

  55. Yang YF, Yang Y, Xie XY, Cai XS, Zhang H, Gong W, et al. PEGylated liposomes with NGR ligand and heat-activable cell-penetrating peptide doxorubicin conjugate for tumor-specific therapy. Biomaterials. 2014;35:4368–81.

    Article  CAS  PubMed  Google Scholar 

  56. Ara MN, Matsuda T, Hyodo M, Sakurai Y, Hatakeyama H, Ohga N, et al. An aptamer ligand based liposomal nanocarrier system that targets tumor endothelial cells. Biomaterials. 2014;35:7110–20.

    Article  CAS  PubMed  Google Scholar 

  57. Li L, ten Hagen TLM, Hossann M, Süss R, van Rhoon GC, Eggermont AMM, et al. Mild hyperthermia triggered doxorubicin release from optimized stealth thermosensitive liposomes improves intratumoral drug delivery and efficacy. J Control Release. 2013;168:142–50.

    Article  CAS  PubMed  Google Scholar 

  58. Zhao Y, Alakhova DY, Kim JO, Bronich TK, Kabanov AV. A simple way to enhance Doxil® therapy: drug release from liposomes at the tumor site by amphiphilic block copolymer. J Control Release. 2013;168:61–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Al-Ahmady ZS, Chaloin O, Kostarelos K. Monoclonal antibody-targeted, temperature-sensitive liposomes: In vivo tumor chemotherapeutics in combination with mild hyperthermia. J Control Release. 2014;196:332–43.

    Article  CAS  PubMed  Google Scholar 

  60. Elias L, Portlock CS, Rosenberg SA. Combination chemotherapy of diffuse histiocytic lymphoma with cyclophosphamide, adriamycin, vincristine and prednisone (CHOP). Cancer. 1978;42:1705–10.

    Article  CAS  PubMed  Google Scholar 

  61. Arndt CAS, Nascimento AG, Schroeder G, Schomberg PJ, Neglia JP, Sencer SF, et al. Treatment of intermediate risk Rhabdomyosarcoma and undifferentiated sarcoma with alternating cycles of vincristine/ doxorubicin/ cyclophosphamide and etoposide/ ifosfamide. Eur J Cancer. 1998;34:1224–9.

    Article  CAS  PubMed  Google Scholar 

  62. Hofmeister CC, Jansak B, Denlinger N, Kraut EH, Benson DM, Farag SS. Phase II clinical trial of arsenic trioxide with liposomal doxorubicin, vincristine, and dexamethasone in newly diagnosed multiple myeloma. Leuk Res. 2008;32:1295–8.

    Article  CAS  PubMed  Google Scholar 

  63. Augustinus DGK, Henrie Ètte WAB, Dew D, Sonja HL, van der Holt B, van’t Veer MB. Cyclophosphamide, doxorubicin, vincristine and prednisone chemotherapy and radiotherapy for stage I intermediate or high grade non-Hodgkin's lymphomas: results of a strategy that adapts radiotherapy dose to the response after chemotherapy. Radiother Oncol. 2001;58:251–5.

    Article  Google Scholar 

  64. Kawasaki H, Taira N, Ichi T, Yohena T, Kawabata T, Ishikawa K. Weekly chemotherapy with cisplatin, vincristine, doxorubicin, and etoposide followed by surgery for thymic carcinoma. EJSO. 2014;40:1151–5.

    Article  CAS  PubMed  Google Scholar 

  65. Maruyama K. Intracellular targeting delivery of liposomal drugs to solid tumors based on EPR effects. Adv Drug Deliv Rev. 2011;63:161–9.

    Article  CAS  PubMed  Google Scholar 

  66. Allen TM, Hansen C, Martin F, Redemann C, Yau-Young A. Liposomes containing synthetic lipid derivatives of poly (ethylene glycol) show prolonged circulation half-lives in vivo. Biochim Biophys Acta. 1991;1066:29–36.

    Article  CAS  PubMed  Google Scholar 

  67. May JP, Li SD. Thermosensitive liposomes in cancer therapy. Recent Pat Biomed Eng. 2012;5:148–58.

    Article  CAS  Google Scholar 

  68. Koning GA, Eggermont AM, Lindner LH, ten Hagen TL. Hyperthermia and thermo-sensitive liposomes for improved delivery of chemotherapeutic drugs to solid tumors. Pharm Res. 2010;27:1750–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Ta T, Porter TM. Thermosensitive liposomes for localized delivery and triggered release of chemotherapy. J Control Release. 2013;169:112–25.

    Article  CAS  PubMed  Google Scholar 

  70. Yatvin MB, Weinstein JN, Dennis WH, Blumenthal R. Design of liposomes for enhanced local release of drugs by hyperthermia. Science. 1978;202:1290–3.

    Article  CAS  PubMed  Google Scholar 

  71. Gaber MH, Hong K, Huang SK, Papahadjopoulos D. Thermosensitive sterically stabilized liposomes: formulation and in vitro studies on mechanism of doxorubicin release by bovine serum and human plasma. Pharm Res. 1995;12:1407–16.

    Article  CAS  PubMed  Google Scholar 

  72. Dordal MS, Winter JN, Atkinson AJJ. Kinetic analysis of P-glycoprotein-mediated doxorubicin efflux. J Pharmacol Exp Ther. 1992;263:762–6.

    CAS  PubMed  Google Scholar 

  73. Celia C, Trapasso E, Cosco D, Paolino D, Fresta M. Turbiscan® Expertanalysis of the stability of ethosomes and ultra deformable liposomes containing a bilayer fluidizing agent. Colloids Surf B: Biointerfaces. 2009;72:155–60.

    Article  CAS  PubMed  Google Scholar 

  74. Yang ZB, Gong W, Wang ZY, Li BS, Li MY, Xie XY, et al. A novel drug-polyethylene glycol liquid compound method to prepare10-hydroxycamptothecin loaded human serum albumin nanoparticle. Int J Pharm. 2015;490:412–28.

    Article  CAS  PubMed  Google Scholar 

  75. Holzgrabe U, Nap CJ, Almeling S. Control of impurities in l-aspartic acid and l-alanine by high-performance liquid chromatography coupled with a corona charged aerosol detector. J Chromatogr A. 2010;1217(3):294–301.

    Article  CAS  PubMed  Google Scholar 

  76. Dunne M, Zheng J, Rosenblat J, Jaffray DA. Allen C.APN/CD 13-targeting as a strategy to alter the tumor accumulation of liposomes. J Control Release. 2011;154:298–305.

    Article  CAS  PubMed  Google Scholar 

  77. Viglianti BL. Target molecular therapies: methods to enhance and monitor tumor drug delivery. Abdom Imaging. 2009;34:686–95.

    Article  PubMed  Google Scholar 

  78. van der Zee J, Gonzalez GD, van Rhoon GC, van Dijk JD, van Putten WL, Hart AA. Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumors: a prospective, randomised, multicentre trial. Dutch Deep Hyperth Group Lancet. 2000;355:1119–25.

    Google Scholar 

  79. Issels RD, Lindner LH, Verweij J, Wust P, Reichardt P, Schem BC, et al. Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study. Lancet Oncol. 2010;11:561–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Song CW. Effect of local hyperthermia on blood flow and microenvironment: a review. Cancer Res. 1984;44:4721s–30s.

    CAS  PubMed  Google Scholar 

Download references

ACKNOWLEDGMENTS AND DISCLOSURES

Authors acknowledge the financial support from Important National Science & Technology Specific Projects (Grant No.2012ZX09301003-001-009) and National Science Foundation of China (No. 81202466). We have no conflicts of interest to declare. And we sincerely thank the reviewers for the many useful suggestions offered to improve this article.

Author information

Author notes

  1. Xingguo Mei & Wei Gong

    Present address: , No.27 Taiping Road, Haidian District, Beijing, China

Authors and Affiliations

  1. Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850, People’s Republic of China

    Mingyuan Li, Zhiping Li, Yang Yang, Zhiyuan Wang, Bingsheng Li, Hui Zhang, Ying Li, Guangyu Gao, Xingguo Mei & Wei Gong

  2. Pharmacy Department, No. 261 Hospital of PLA, Beijing, 100094, People’s Republic of China

    Zhenbo Yang

  3. Department of Pharmacy, Wuhan General Hospital of Guangzhou Military Command, Wuhan, 430070, People’s Republic of China

    Xiangyang Xie

  4. Institute of Transfusion Medicine, Academy of Military Medical Sciences, Beijing, 100850, People’s Republic of China

    Jinwen Song

  5. School of Pharmacy, Yunnan University of Traditional Chinese Medicine, Kunming, 650500, People’s Republic of China

    Jingyuan Yang

Authors
  1. Mingyuan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhiping Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yang Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhiyuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhenbo Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bingsheng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiangyang Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jinwen Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hui Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ying Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Guangyu Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jingyuan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Xingguo Mei
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Wei Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Xingguo Mei or Wei Gong.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, M., Li, Z., Yang, Y. et al. Thermo-Sensitive Liposome co-Loaded of Vincristine and Doxorubicin Based on Their Similar Physicochemical Properties had Synergism on Tumor Treatment. Pharm Res 33, 1881–1898 (2016). https://doi.org/10.1007/s11095-016-1924-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-016-1924-2

KEY WORDS

Search

Navigation